HAPSTR1 (C16orf72) is a central coordinator of cellular stress responses that functions as a negative regulator of p53. The protein acts as a molecular rheostat within an integrated network of stress response pathways, titrating cellular adaptation to diverse stressors including DNA damage, nutrient scarcity, and proteotoxicity 1. HAPSTR1 negatively regulates both wild-type p53 and p53 mutants, buffering against deleterious p53 activation during telomere erosion and DNA damage 23. Mechanistically, HAPSTR1 exists as two isoforms that oligomerize and bind the E3 ubiquitin ligase HUWE1, which is required for HAPSTR1's stress-signaling function; HUWE1 paradoxically marks HAPSTR1 for degradation in a feedback loop 1. Additional regulators include TRIP12 and USP7, which titrate HAPSTR1 stability, while HAPSTR2, a mammalian retrogene, stabilizes HAPSTR1 and buffers its loss 4. HAPSTR1 overexpression is common in breast and ovarian cancers, promoting proliferation and metastasis through suppression of p53 and modulation of autophagy 35. Notably, HAPSTR1 is essential for mammalian life independent of p53 suppression, as Hapstr1-null mice are perinatal lethal 6, indicating p53-independent functions in nuclear protein quality control remain incompletely understood.